Targeting Default Mode Network Dysfunction in Persons at Risk of Alzheimer's Disease With Non-invasive Techniques (NEST4AD)

September 18, 2023 updated by: Michela Pievani, IRCCS Centro San Giovanni di Dio Fatebenefratelli
Default mode network (DMN) dysfunction is a well-established feature of Alzheimer's Disease (AD) and is already present in preclinical stages and in subjects at risk for AD, thus offering a potential target for early intervention. Non-invasive stimulation techniques are candidate approaches to modulate network dysfunction, however interventions specifically targeting subjects at risk for AD are lacking. This project will test a non-invasive intervention to modulate the DMN in cognitively healthy older adults carrying the main genetic risk factor for AD, the APOE e4 allele. The proposal will non-invasively stimulate the DMN in at risk subjects and will assess the neuronal-cognitive effect of this approach with multimodal neuroimaging and neurophysiological techniques.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Sixty-four participants will be enrolled (n=32 APOE e4 carriers, 32 non-carriers as reference group) and will undergo rTMS stimulation, TMS with concurrent electroencephalography (TMS-EEG), multimodal imaging (resting-state and task functional MRI, and diffusion tensor imaging) and cognitive assessment at baseline, after the intervention (week 1) and after 2 months. Participants will be randomized to 2 groups: active DMN stimulation (real-rTMS) or placebo (sham-rTMS). Each subject will undergo a rs-fMRI scan before the intervention to derive individualized DMN stimulation targets. rTMS will be applied over the left inferior parietal lobule node of the DMN.

Study Type

Interventional

Enrollment (Estimated)

64

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Italy
      • Brescia, Italy, 25125
        • Recruiting
        • IRCCS Centro San Giovanni di Dio Fatebenefratelli
        • Contact:
        • Principal Investigator:
          • Michela Pievani, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Age: 60 years and older
  • MMSE score > 24

Exclusion Criteria:

  • Pathological scores in at least two standardized cognitive tests
  • Participation in other interventional studies
  • Known carriers of an autosomal dominant genetic mutation associated to AD
  • Neurological, psychiatric or medical conditions not compatible with the study

Exclusion Criteria for MRI and rTMS:

  • metal implants, pace-makers, prosthetic heart valves
  • claustrophobia
  • history of epilepsy
  • pregnancy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: real-rTMS
4 daily 25-minutes high-frequency rTMS sessions over one week
Device: real-rTMS
Each subject will undergo 4 rTMS sessions using a 70-mm figure-eight coil (20Hz for 25 minutes). Target localization will be performed with a stereotaxic neuronavigation system.
Sham Comparator: sham-rTMS
4 daily 25-minutes sham-rTMS sessions over one week
Device: sham-rTMS
The sham condition will match the real-rTMS protocol, but a sham coil will be used.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in DMN connectivity on rs-fMRI following real-rTMS compared to sham-rTMS in APOE4 carriers
Time Frame: Baseline, post rTMS (1 week)
Default mode network (DMN) mean functional connectivity is assessed on resting state functional MRI. Higher values denote greater functional connectivity. A positive change at post rTMS compared to baseline represents an increase in resting-state functional connectivity.
Baseline, post rTMS (1 week)
Change in DMN connectivity on TMS-EEG following real-rTMS compared to sham-rTMS in APOE4 carriers
Time Frame: Baseline, post rTMS (1 week)
Single pulse TMS will be applied with concurrent EEG to derive online measures of cortical excitability and connectivity. The response in the natural frequency of the target area will index cortical excitability. Effective connectivity will be measured through amplitude and latency of TEPs.
Baseline, post rTMS (1 week)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in task-fMRI associative memory performance following real-rTMS compared to sham-rTMS in APOE4 carriers
Time Frame: Baseline, post rTMS (1 week)
Memory is assessed on task fMRI using a face-name associative paradigm
Baseline, post rTMS (1 week)

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in DMN connectivity on rs-fMRI following real-rTMS in APOE4 carriers compared to non-carriers
Time Frame: Baseline, post rTMS (1 week)
Default mode network (DMN) mean functional connectivity is assessed on resting state functional MRI. Higher values denote greater functional connectivity. A positive change at post rTMS compared to baseline represents an increase in resting-state functional connectivity.
Baseline, post rTMS (1 week)
Change in task-fMRI associative memory performance following real-rTMS in APOE4 carriers compared to non-carriers
Time Frame: Baseline, post rTMS (1 week)
Memory is assessed on task fMRI using a face-name associative paradigm
Baseline, post rTMS (1 week)
Change in cognition following real-rTMS in APOE4 carriers compared to non-carriers
Time Frame: Baseline, post rTMS (1 week)
Cognition is assessed with the MMSE, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Free and Cued Selective Reminding Test (FCSRT), and the preclinical Alzheimer cognitive composite (PACC) score.
Baseline, post rTMS (1 week)
Change in cognition following real-rTMS compared to sham-rTMS in APOE4 carriers
Time Frame: Baseline, post rTMS (1 week)
Cognition is assessed with the MMSE, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Free and Cued Selective Reminding Test (FCSRT), and the preclinical Alzheimer cognitive composite (PACC) score.
Baseline, post rTMS (1 week)
Change in cognition following real-rTMS compared to sham-rTMS in APOE4 carriers
Time Frame: Baseline, post rTMS (2 months)
Cognition is assessed with the MMSE, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Free and Cued Selective Reminding Test (FCSRT), and the preclinical Alzheimer cognitive composite (PACC) score.
Baseline, post rTMS (2 months)
Change in DMN connectivity on TMS-EEG following real-rTMS in APOE4 carriers compared to non-carriers
Time Frame: Baseline, post rTMS (1 week)
Single pulse TMS will be applied with concurrent EEG to derive online measures of cortical excitability and connectivity. The response in the natural frequency of the target area will index cortical excitability. Effective connectivity will be measured through amplitude and latency of TEPs.
Baseline, post rTMS (1 week)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

IRCCS Centro San Giovanni di Dio Fatebenefratelli

Investigators

  • Principal Investigator: Michela Pievani, IRCCS Centro San Giovanni di Dio Fatebenefratelli

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 5, 2019

Primary Completion (Estimated)

June 30, 2024

Study Completion (Estimated)

December 4, 2024

Study Registration Dates

First Submitted

August 2, 2023

First Submitted That Met QC Criteria

August 2, 2023

First Posted (Actual)

August 9, 2023

Study Record Updates

Last Update Posted (Actual)

September 21, 2023

Last Update Submitted That Met QC Criteria

September 18, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GR-2018-12368250

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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